Project Summary/Abstract Contemporaneous urban vector control (truck-mounted ultra-low volume spraying, thermal fogging, larviciding) has failed to contain dengue epidemics and to prevent the global range expansion of Aedes- borne viruses (ABVs: dengue, chikungunya, Zika). Part of the challenge in sustaining effective ABV control emerges from the remarkable paucity of evidence about the epidemiological impact of any vector control method. Furthermore, the classic deployment of interventions in response to clinical cases fails to account for the important contribution of out-of-home human mobility and asymptomatic infections. Novel vector control approaches and intervention delivery strategies to contain ABVs are urgently needed. Targeted indoor residual spraying (TIRS, applying residual insecticides on Aedes aegypti resting sites such as exposed low walls [<1.5m], under furniture, and on dark surfaces) is a rational vector control approach that exploits Ae. aegypti resting behavior to focalize insecticide applications with no loss in residual efficacy. Recently published systematic reviews have identified TIRS as a very promising approach for ABD prevention, but highlighted the limited evidence-base for this intervention due to the absence of efficacy estimates from randomized controlled trials with epidemiological endpoints performed in endemic settings. In response to such critical need, we will pursue a two-arm, parallel, unblinded cluster randomized trial to quantify the overall efficacy of TIRS in reducing the burden of laboratory- confirmed (virologically or serologically) ABV clinical disease (e.g., dengue, Zika or chikungunya) (primary endpoint). Secondary endpoints will include: a) Laboratory-confirmed (serologically) DENV, CHIKV or ZIKV seroconversion in children aged 2-15 at enrollment; b) Ae. aegypti mosquito infection rates with DENV, CHIKV or ZIKV; c) Ae. aegypti indoor entomological indices. The trial will be conducted in the city of Merida (Yucatan State, Mexico, population ~1million), where we will prospectively follow a population of 4,600 children 2-15 years at enrollment, distributed in 50 clusters of 5x5 city blocks each (~92 children per cluster), randomly allocated to receive either TIRS treatment (n=25) or not (n=25). Trained personnel from the Federal Ministry of Health will perform TIRS in all houses from the treatment clusters ~1-2 months prior to the beginning of the peak ABV transmission season. Active monitoring for symptomatic ABD infections will be performed by field nurses and doctors through weekly household visits and enhanced surveillance (phone calls, monitoring of suspected cases to Merida?s hospital/clinic system), whereas annual sero-surveys will be performed after each transmission season. If efficacious, TIRS will drive a paradigm shift in Aedes control by: considering Ae. aegypti behavior to guide insecticide applications; change to preemptive control (pre- ABV transmission season rather than in response to symptomatic cases); the use of insecticide formulations to which Ae. Aegypti is susceptible.